Ultrasonic Neuromodulation for Alzheimer's Disease

Overseen By Jan Kubanek, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Utah

Disqualifiers: Stroke, Suicidal ideation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Diadem prototype for Alzheimer's Disease?

Research shows that transcranial pulse stimulation (TPS), a type of ultrasound brain treatment, can improve memory and cognitive function in Alzheimer's patients for up to three months. It also helps reduce depressive symptoms and is well-tolerated with no major side effects. ^{1 2 3 4 5}

Is ultrasonic neuromodulation safe for humans?

Ultrasonic neuromodulation, including techniques like transcranial pulse stimulation (TPS) and low intensity focused ultrasound (LIFU), has been studied for safety in humans. Studies show that these methods are generally well-tolerated with no major side effects, although some participants reported mild symptoms like neck pain and headaches, which were temporary. Overall, the safety profile is similar to other non-invasive brain stimulation methods. ^{1 3 4 6 7}

How does the treatment Diadem prototype differ from other treatments for Alzheimer's disease?

The Diadem prototype uses ultrasonic neuromodulation, a novel non-invasive technique that uses ultrasound waves to target and modulate brain activity, which is different from traditional drug-based treatments. This method can focus on specific brain areas with high precision, potentially improving memory networks and cognitive function without major side effects. ^{1 3 8 9 10}

What is the purpose of this trial?

This study will evaluate a new form of non-invasive deep brain therapy for individuals with Alzheimer's disease. Low-intensity transcranial focused ultrasound stimulation will first be delivered using a range of stimulation parameters during psychophysical and physiological monitoring. A well-tolerated stimulation protocol will be selected for subsequent testing in a blinded randomized sham-controlled cross-over trial. The trial will evaluate brain target engagement using magnetic resonance imaging, PET imaging, and numerical scales of cognitive performance.

Eligibility Criteria

This trial is for individuals aged 65-80 with mild cognitive impairment or early-stage dementia due to Alzheimer's, confirmed by specific biomarkers. Participants must have a certain level of cognitive function (MOCA > 18) and be able to complete an MRI. Those with recent strokes, other brain diseases, or suicidal thoughts cannot join.

Inclusion Criteria

I have mild memory problems or mild dementia due to Alzheimer's, confirmed by tests.

I am between 65 and 80 years old.

MOCA > 18

Exclusion Criteria

Suicidal ideation

I cannot undergo an MRI scan.

I have had a stroke or been diagnosed with cerebral amyloid angiopathy in the last year.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Stimulation and Monitoring

Low-intensity transcranial focused ultrasound stimulation delivered with various parameters during psychophysical and physiological monitoring

4 weeks

Multiple visits for parameter testing and monitoring

Blinded Randomized Sham-Controlled Cross-Over Trial

Testing of selected stimulation protocol in a blinded randomized sham-controlled cross-over trial

8 weeks

Regular visits for treatment and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment using cognitive assessments and imaging

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Diadem prototype

Trial Overview The study tests the Diadem prototype, which uses low-intensity ultrasound waves aimed at the brain to improve cognition in Alzheimer's patients. It includes initial testing to find a safe protocol followed by a blinded comparison where some get real treatment and others don't.

Participant Groups

Group I: Active stimulation Experimental Treatment 1 Intervention

Low-intensity transcranial focused ultrasound stimulation of deep brain targets affected by Alzheimer's disease.

Group II: Sham stimulation Placebo Group 1 Intervention

Sham stimulation that applies the device in the same way as verum but only delivers auditory sounds correspoding to the ultrasonic pulses.

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Findings from Research

The new transcranial pulse stimulation (TPS) technique using ultrashort ultrasound pulses shows promising safety and efficacy in modulating brain activity, with preclinical studies indicating large safety margins and effective neuromodulation.

In a clinical pilot study involving 35 Alzheimer's patients, TPS treatment led to significant improvements in neuropsychological scores, with effects lasting up to three months and correlating with enhanced memory network activity as shown by fMRI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy. Beisteiner, R., Matt, E., Fan, C., et al.[2023]

In a study of 18 Alzheimer's disease patients, transcranial pulse stimulation (TPS) significantly improved depressive symptoms as measured by the Beck Depression Inventory (BDI-II) after 2-4 weeks of treatment.

Functional connectivity analysis revealed that TPS normalized connections between brain networks associated with emotion and cognition, suggesting that this non-invasive therapy could be an effective add-on treatment for depression in Alzheimer's patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial pulse stimulation (TPS) improves depression in AD patients on state-of-the-art treatment. Matt, E., Dörl, G., Beisteiner, R.[2022]

The study introduces a novel transcranial focused ultrasound stimulation (tFUS) system that allows for chronic, closed-loop neuromodulation in freely behaving rodents, overcoming limitations of previous preclinical models.

Using this system, researchers found that ultrasound stimulation of the prefrontal cortex can enhance REM sleep and protect spatial working memory during REM sleep deprivation, suggesting potential therapeutic applications for brain disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

General-Purpose Ultrasound Neuromodulation System for Chronic, Closed-Loop Preclinical Studies in Freely Behaving Rodents. Jo, Y., Lee, SM., Jung, T., et al.[2022]

In a study involving 12 healthy participants, transcranial pulse stimulation (TPS) was shown to significantly enhance the efficiency of the cortical sensorimotor network and improve axonal status in the stimulated area, indicating positive neuroplastic changes.

The effects of TPS were observed to last up to one week after stimulation, suggesting its potential for long-term benefits in treating neurological and psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First evidence of long-term effects of transcranial pulse stimulation (TPS) on the human brain. Matt, E., Kaindl, L., Tenk, S., et al.[2022]

Transcranial pulse stimulation (TPS) therapy over 2-4 weeks showed improvements in cognitive performance and functional networks in Alzheimer's disease (AD) patients, with effects lasting up to 3 months.

In a study of 17 AD patients, an increase in cortical thickness was significantly correlated with neuropsychological improvements, suggesting that TPS may help reduce cortical atrophy in critical brain areas associated with memory.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial ultrasound pulse stimulation reduces cortical atrophy in Alzheimer's patients: A follow-up study. Popescu, T., Pernet, C., Beisteiner, R.[2023]

A study involving 120 participants evaluated the safety of low intensity transcranial focused ultrasound (LIFU) for neuromodulation, finding no serious adverse effects and only mild to moderate symptoms reported by 7 participants, which were generally transient.

The symptom profile from LIFU was similar to other non-invasive brain stimulation methods, suggesting that LIFU is a safe option for neuromodulation with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. Legon, W., Adams, S., Bansal, P., et al.[2021]

Transcranial ultrasound stimulation (TUS) can non-invasively target both cortical and deep brain structures with high spatial resolution, potentially allowing for precise neuromodulation that was previously only possible with invasive methods.

The mechanism of TUS involves ultrasound waves interacting with neuronal membranes, leading to changes in neuronal excitability, which could have significant implications for both basic research and clinical applications in neuromodulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive transcranial ultrasound stimulation for neuromodulation. Darmani, G., Bergmann, TO., Butts Pauly, K., et al.[2022]

Ultrasonic waves can be precisely directed and focused to modulate neuronal activity non-invasively, which could revolutionize approaches in neural science and engineering.

Recent studies have shown that ultrasonic neuro-modulation can directly excite or suppress neural activity in both animal models and humans, highlighting its potential for therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasonic neuromodulation. Naor, O., Krupa, S., Shoham, S.[2022]

A new chip-scale device using GHz ultrasonic waves has been developed to stimulate human neural cells, showing promise for improved localization and control in neural prosthetics.

This study is the first to demonstrate that GHz ultrasound can effectively stimulate neurons in vitro without significant thermal effects, indicating a safe and innovative approach for future neural engineering applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GHz Ultrasonic Chip-Scale Device Induces Ion Channel Stimulation in Human Neural Cells. Balasubramanian, PS., Singh, A., Xu, C., et al.[2021]

Ultrasound (US) has emerged as a promising non-invasive method to modulate neuronal activity, showing potential to stimulate or suppress nerve function in various models, including peripheral nerves and brain circuits.

The mechanism of action involves the interaction of ultrasound with mechanosensitive ion channels, and its ability to focus on deep-brain regions with high precision makes it a valuable tool for developing advanced neurotechnologies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasonic modulation of neural circuit activity. Tyler, WJ., Lani, SW., Hwang, GM.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Transcranial pulse stimulation (TPS) improves depression in AD patients on state-of-the-art treatment. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

General-Purpose Ultrasound Neuromodulation System for Chronic, Closed-Loop Preclinical Studies in Freely Behaving Rodents. [2022]

4. England pubmed.ncbi.nlm.nih.gov

First evidence of long-term effects of transcranial pulse stimulation (TPS) on the human brain. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Transcranial ultrasound pulse stimulation reduces cortical atrophy in Alzheimer's patients: A follow-up study. [2023]

6. England pubmed.ncbi.nlm.nih.gov

A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Non-invasive transcranial ultrasound stimulation for neuromodulation. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Ultrasonic neuromodulation. [2022]

9. England pubmed.ncbi.nlm.nih.gov

GHz Ultrasonic Chip-Scale Device Induces Ion Channel Stimulation in Human Neural Cells. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Ultrasonic modulation of neural circuit activity. [2019]